c-Cbl is involved in Met signaling in B cells and mediates hepatocyte growth factor-induced receptor ubiquitination.

Hepatocyte growth factor/scatter factor (HGF) and its receptor tyrosine kinase Met are key regulators of epithelial motility and morphogenesis. Recent studies indicate that the HGF/Met pathway also plays a role in B cell differentiation, whereas uncontrolled Met signaling may lead to B cell neoplasia. These observations prompted us to explore ...
HGF/Met signaling in B cells. In this study, we demonstrate that HGF induces strong tyrosine phosphorylation of the proto-oncogene product c-Cbl in B cells and increases Cbl association with the Src family tyrosine kinases Fyn and Lyn, as well as with phosphatidylinositol-3 kinase and CrkL. In addition, we demonstrate that c-Cbl mediates HGF-induced ubiquitination of Met. This requires the juxtamembrane tyrosine Y1001 (Y2) of Met, but not the multifunctional docking site (Y14/15) or any additional C-terminal tyrosine residues (Y13-16). In contrast to wild-type c-Cbl, the transforming mutants v-Cbl and 70Z/3 Cbl, which lack the ubiquitin ligase RING finger domain, suppress Met ubiquitination. Our findings identify c-Cbl as a negative regulator of HGF/Met signaling in B cells, mediating ubiquitination and, consequently, proteosomal degradation of Met, and suggest a role for Cbl in Met-mediated tumorigenesis.
Mesh Terms:
1-Phosphatidylinositol 3-Kinase, Adaptor Proteins, Signal Transducing, Animals, B-Lymphocytes, COS Cells, Cell Membrane, Hepatocyte Growth Factor, Humans, Ligases, Nuclear Proteins, Phosphorylation, Phosphotyrosine, Proto-Oncogene Proteins, Proto-Oncogene Proteins c-cbl, Proto-Oncogene Proteins c-fyn, Proto-Oncogene Proteins c-met, Signal Transduction, Substrate Specificity, Tumor Cells, Cultured, Ubiquitin-Protein Ligases, Ubiquitins, src-Family Kinases
J. Immunol.
Date: Oct. 01, 2002
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